DESCRIPTION The specificity of neuronal connections is striking and reproducible but the molecular cues that govern their creation are largely unknown. Little is understood about the mechanisms that induce neurons to accept inputs from particular synaptic partners but to ignore others. In the nematode C. elegans, VA and VB motor neurons arise from a common precursor but synapse with separate sets of interneurons. In unc-4 mutants, VA motor neurons receive synaptic inputs normally reserved for their VB sister cells. The UNC-4 homeoprotein is expressed in the VA motor neurons and its function depends on the simultaneous presence of UNC-37, a homolog of the transcriptional corepressor protein, Groucho. The PI has proposed that UNC-4 and UNC-37 function together in the VA motor neurons to negatively regulate genes that specify VB-type inputs, thereby insuring the creation of VA-type inputs. This proposal aims to test this model and to molecularly define the genes that unc-4 and unc-37 regulate. Ectopic expression of UNC-4 in VB motor neurons produces a specific "uncoordinated" phenotype that suggests the VBs have been respecified to receive VA-type inputs. The major goals of the proposal are: 1) to use ultrastructural and functional assays to directly determine if the VB motor neuron circuit has been rewired in this manner; 2) to ectopically express two VB-specific genes, del-1 and acr-4 (an AChR subunit), that are negatively regulated by UNC-4 and UNC-37 in the VAs. These unc-4 target genes will be ectopically expressed in the VAs in order to determine if either induces VB-type inputs; 3) to molecularly define bkn-1 and bkn-2, which are suppressors of unc-4 and unc-37, respectively.